The next three routes use PCA (1-phenyl cyclohexylamine) as
a precursor for either PCP or other analogs.

PCA itself is an active compound, and has been under clinical
study as a potential anesthetic agent. It is approximately one
half as potent than PCP and appears to have similar actions. PCA
can be transformed into other PCP analogs by alkylation of the
amino group by a number of methods. It is possible to react 1,5-dibromopentane
with PCA in order to create PCP (yield 65-75% after 1-6 days;
ref. 10, 11, 50-56).
Reaction of PCA with formic acid and formaldehyde gives the N,N-dimethyl
analog of PCP (ref. 10).
An attractive procedure from the standpoint of clandestine synthesis
would be the reductive alkylation of PCA with acetone and aluminum
amalgam to give the potent analog N-isopropyl phenylcyclohexylamine.

The first method using PCA as an intermediate is Scheme
IV. This route has received little attention among clandestine
chemists, but has potential for synthesis of PCP derivatives without
use of watched chemicals. This route gives an overall yield of
~40% with a difficulty rating of 7 out of 10, and a hazard rating
of 8 out of 10 (ref. 64).

The PCOH starting material can be purchased or prepared by
reaction of phenyllithium or phenyl grignard with cyclohexanone.
This alcohol is then be transformed into the amine by reaction
with sodium azide (~90% yield) followed by reduction. The azide
is easily reduced to the final amine by a number of reagents,
such as Raney Nickel, Pd/C, magnesium metal, lithium aluminum
hydride, or sodium borohydride (ref.
50-54).

One of the better procedures for formation of the azide involves
adding the alcohol to a suspension of sodium azide in trichloroacetic
or trifluoroacetic acid (ref.
39). Another reagent that has been used to form the azide
is diisopropylazodicarboxylate (ref.
55). It should be noted that sodim azide is highly toxic,
and contact with acid will release the even more deadly hydrazoic
acid.

Reaction
Scheme V. PCP via Ritter reaction:

This method is generally easy, and starts with inexpensive
and commercially available 1-phenylcyclohexene, or alternately
from1-phenylcyclohexanol (PCOH) (ref.
10, 56, 58, 65). PCOH or phenylcyclohexene is reacted with
sodium cyanide and H2SO4 to give N-formyl PCA in about 50-60%
yield. N-formyl PCA is readily hydrolyzed in either acid or base
conditions to give PCA, which can then be alkylated to give PCP
and other analogs, as illustrated in Scheme
IV. This route has an overall yield of ~30% with a difficulty
rating of 1-2 out of 10, and a hazard rating of 3 out of 10 (ref. 64).

Reaction Scheme V. PCP via a Ritter
reaction:

Procedure (ref. 11):

Preparation of PCA: To a mixture of 15.8 gm of 1-phenylcyclohexene
(0.1 mole) and 12.2 gm of NaCN (0.25 mole) in 50 mL of dibutyl
ether, was added 30 mL of H2SO4 over 1 hr. After stirring for
an additional 1 hr, the reaction mixture was poured into water
and extracted with ether. The solvents were removed in vacuo,
30 mL of HCl was added to the residue, and the mixture refluxed
for 3 hrs. After cooling, the aqueous layer was seperated, basified
with NaOH, and extracted with ether. The HCl salt was prepared
by adding dry HCl in isopropanol, followed by evaporation. 20
mL of acetone was then added to the residue, followed by recrystallization
twice from methanol/ether to give needles (mp 247-248 C).

Preparation of PCP from PCA: A mixture of 8.69 gm of
PCA, 11.5 gm of 1,5-dibromopentane, and 8.0 gm of anhydrous K2CO3
in 50 mL of dry DMF was stirred and heated. At 50-55 C an exothermic
reaction took place and the temperature rose to 95-100 C. The
flask was heated for 1 hr on a steam bath, poured into ice cold
water and extracted with ether, followed by distillation and
recrystallization to give the final compound.

Reaction Scheme VI. PCP via phenylacetonitrile:

This reaction starts with low cost materials, but the procedure
is more lengthy, difficult, and dangerous than previous methods.
Overall yield is around 30%, with a difficulty rating of 9 out
of 10, and a hazard rating of 8 out of 10 (ref.
64, 10).

Reaction Scheme VI. PCP via phenylacetonitrile:

The starting material is phenylacetonitrile (benzyl cyanide),
which is a watched precursor for methamphetamine synthesis. It
can, however be easily
synthesized from benzyl chloride and NaCN. Benzyl chloride
can also be prepared without much difficulty, by the chlorination
of toluene. Also certain (unwatched) substituted phenylacetonitriles
could be used to yield potent PCP analogs, e.g. 3-methoxyphenylacetonitrile.

Chemistry: In the first step, phenylacetonitrile is
reacted with 1,5-dibromopentane and strong base to yield 1-phenyl-1-cyclohexanecarbonitrile.
The base can be either NaNH2 (sodamide; 65% yield) or sodium hydride
in anhydrous DMSO (better). If NaNH2 is used it may be purchased
commercially or prepared from sodium metal and liquid ammonia
(-30 C).

In the next step, the carbonitrile is hydrolyzed with either
HCl or H2SO4 in trifluoroacetic acid to give 1-phenyl-1-cyclohexanecarboxamide
(yield 85%; ref. 10).
Some substituted phenylacetonitriles are extremely resistant to
acid hydrolysis, in which case basic hydrolysis may be more efficient
(ref. 62).

Finally, the amide is subjected to a Beckmann rearrangement,
giving N-formyl PCA, and the formyl group is hydrolyzed, to yield
PCA in about 80% yield (ref.
63, 56). The PCA can be transformed into PCP or other analog
as illustrated in Scheme V.

Procedure.

Step 1: 1-phenylcyclohexanecarbonitrile: A mixture
of 222 gm (1.9 moles) of phenylacetonitrile and 400 gm (1.71
moles) of 1,5-dibromopentane was added over 6 hrs. to a refluxing
suspension of 593 gm (7.54 moles) of sodamide in 4.5 L of ether.
Reflux was continued overnight, followed by cooling in an ice
bath and addition of 1.6 L of water over a period of 2.5 hrs,
keeping the temperature at 21-24 C. The mixture was then refluxed
for 1 hr. and cooled. Following filtration and seperation of
the aqueous layer, the ether layer was washed with 1 L of water
and 1 L of 3 N HCl. The solvent was then distilled to
give 234 (72% yield) of crude product. Purification by fractional
distillation (102 C / 0.1 mm Hg) gave 62% of pure nitrile.

Step 2: 1-phenylcyclohexanecarboxamide: A mixture of
130 g (0.7 mole) of 1-phenylcyclohexanecarbonitrile, 415 g of
trifluoroacetic acid, and 59.5 g of H2SO4 was heated at reflux
for 16 hrs., and then poured onto 500 gm of ice. A tan precipitate
will form, which is washed with water, saturated aqueous Na2CO3,
and then water again until neutral. The crude product weighed
121 gm (85.5% yield), and recrystallization from isooctane or
hexane gives 72.3 gm of amide (50.8% yield), mp 85-88 C.

Step 3: 1-phenylcyclohexylamine (PCA): To a cooled
solution of 198 gm of KOH in 1 L of water was added 18 mL of
bromine, and the solution further cooled to 7 C. 67.3 gm (0.331
mole) of 1-phenylcyclohexanecarboxamide was added at once, and
the mixture held at 3-9 C for 90 min. with stirring. It was then
extracted 3 times with 200 mL of ether, 300 mL of concentrated
HCl was heated to 50 C, and the extracts added. The mixture was
heated to 110 C for 90 min., cooled to 85 C, and 210 gm of NaOH
in 900 mL of water was added over 15 min. After cooling and extracting
with 600 mL of ether, the solution was dried over NaOH pellets
and the ether distilled to give a residue of crude amine (46.4
gm, 80.3% yield).